Reaction Steps
A solution of 4-bromo-2-fluoropyridine (2.0 g, 11.3 mmol) and n-butan-1-amine (752 mg, 10.3 mmol) in N-methyl-2-pyrrolidinone (NMP, 10 mL) was stirred at 100° C. for 1 hr. The reaction was allowed to cool to room temperature and diluted with DCM (50 mL), washed with water (10 mL*2). The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (0-20% EtOAc-petroleum ether gradient elution) to afford the desired product (1.4 g, 45%). 1H NMR (300 MHz, CDCl3): 7.88 (d, J=5.4 Hz, 1H), 6.70 (d, J=5.4 Hz, 1H), 6.54 (s, 1H), 4.60 (br s, 1H), 3.26-3.19 (m, 2H), 1.63-1.56 (m, 2H), 1.46-1.39 (m, 2H), 0.96 (t, J=7.2 Hz, 3H). (R)-tert-butyl 1-(2-(butylamino)pyridin-4-yl)pyrrolidin-3-ylcarbamate. To a solution of 4-bromo-N-butylpyridin-2-amine (458 mg, 2 mmol), (R)-tert-butyl pyrrolidin-3-ylcarbamate (410 mg, 2.2 mmol) in anhydrous dioxane (12 mL) was added Pd2(dba)3 (200 mg, 0.22 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (Xant-phos) (200 mg, 0.24 mmol) and t-BuONa (576 mg, 6 mmol) under atmosphere of argen. The resulting reaction was stirred at 100° C. for 2 hrs and diluted with water (40 mL), extracted with DCM, The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (0-10% MeOH-DCM gradient elution) to afford the crude product (purity>70%). (R)-4-(3-aminopyrrolidin-1-yl)-N-butylpyridin-2-amine dihydrochloride. Crude product obtained above was dissolved in MeOH (6 mL) and ether solution of HCl gas (ca. 4N, 10 mL) was added. The resulting reaction was stirred at ambient temperature for 20 hrs. The reaction was concentrated under reduced pressure and purified by prep-HPLC to afford the desired product (50 mg, 6.7% yield in two steps). 1H NMR (300 MHz, CD3OD): 7.59 (d, J=7.5 Hz, 1H), 6.39 (d, J=6.9 Hz, 1H), 5.79 (s, 1H), 4.89 (m, 1H), 4.15 (m, 1H), 3.74-3.66 (m, 3H), 3.38-3.29 (m, 2H), 2.60-2.53 (m, 1H), 2.34-2.30 (m, 1H), 1.73-1.64 (m, 2H), 1.56-1.46 (m, 2H), 1.02 (t, J=7.5 Hz, 3H); LC-MS: m/z=235.2 [M+H]+, tR=0.92 min; HPLC: 100% (214 nm), 97% (254 nm), tR=4.84 min. The compounds in Example 255 through Example 297 were prepared using methods analogous to those described in Example 254.
